FURIN_RAT
ID FURIN_RAT Reviewed; 793 AA.
AC P23377;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1991, sequence version 1.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=Furin;
DE EC=3.4.21.75 {ECO:0000269|PubMed:9252368};
DE AltName: Full=Dibasic-processing enzyme;
DE AltName: Full=Paired basic amino acid residue-cleaving enzyme;
DE Short=PACE;
DE AltName: Full=Prohormone convertase 3;
DE Flags: Precursor;
GN Name=Furin; Synonyms=Fur, Pcsk3;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Wistar; TISSUE=Liver;
RX PubMed=2251148; DOI=10.1093/nar/18.22.6719;
RA Misumi Y., Sohoda M., Ikehara Y.;
RT "Sequence of the cDNA encoding rat furin, a possible propeptide-processing
RT endoprotease.";
RL Nucleic Acids Res. 18:6719-6719(1990).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, TISSUE SPECIFICITY, AND
RP INDUCTION BY MECHANICAL STRETCH.
RX PubMed=9252368; DOI=10.1074/jbc.272.33.20545;
RA Sawada Y., Suda M., Yokoyama H., Kanda T., Sakamaki T., Tanaka S.,
RA Nagai R., Abe S., Takeuchi T.;
RT "Stretch-induced hypertrophic growth of cardiocytes and processing of
RT brain-type natriuretic peptide are controlled by proprotein-processing
RT endoprotease furin.";
RL J. Biol. Chem. 272:20545-20554(1997).
RN [3]
RP INTERACTION WITH PACS1.
RC TISSUE=Brain;
RX PubMed=9695949; DOI=10.1016/s0092-8674(00)81420-8;
RA Wan L., Molloy S.S., Thomas L., Liu G., Xiang Y., Rybak S.L., Thomas G.;
RT "PACS-1 defines a novel gene family of cytosolic sorting proteins required
RT for trans-Golgi network localization.";
RL Cell 94:205-216(1998).
CC -!- FUNCTION: Ubiquitous endoprotease within constitutive secretory
CC pathways capable of cleavage at the RX(K/R)R consensus motif
CC (PubMed:9252368). Mediates processing of TGFB1, an essential step in
CC TGF-beta-1 activation (By similarity). Converts through proteolytic
CC cleavage the non-functional Brain natriuretic factor prohormone into
CC its active hormone BNP(1-45) (PubMed:9252368). By mediating processing
CC of accessory subunit ATP6AP1/Ac45 of the V-ATPase, regulates the
CC acidification of dense-core secretory granules in islets of Langerhans
CC cells (By similarity). {ECO:0000250|UniProtKB:P09958,
CC ECO:0000250|UniProtKB:P23188, ECO:0000269|PubMed:9252368}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Release of mature proteins from their proproteins by cleavage
CC of -Arg-Xaa-Yaa-Arg-|-Zaa- bonds, where Xaa can be any amino acid and
CC Yaa is Arg or Lys. Releases albumin, complement component C3 and von
CC Willebrand factor from their respective precursors.; EC=3.4.21.75;
CC Evidence={ECO:0000269|PubMed:9252368};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000250|UniProtKB:P09958};
CC Note=Binds 3 calcium ions per subunit. {ECO:0000250|UniProtKB:P09958};
CC -!- ACTIVITY REGULATION: Inhibited by the not secondly cleaved propeptide
CC (By similarity). Inhibited by m-guanidinomethyl-phenylacetyl-Arg-Val-
CC Arg-(amidomethyl)-benzamidine (m-guanidinomethyl-Phac-RVR-Amb) and 4-
CC guanidinomethyl-phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148)
CC (By similarity). Inhibited by Decanoyl-Arg-Val-Lys-Arg-
CC chloromethylketone (decanoyl-RVKR-CMK) (PubMed:9252368). Inhibited by
CC heparin/heparan sulfate-binding (By similarity).
CC {ECO:0000250|UniProtKB:P09958, ECO:0000269|PubMed:9252368}.
CC -!- SUBUNIT: Interacts with FLNA (By similarity). Binds to PACS1 which
CC mediates TGN localization and connection to clathrin adapters
CC (PubMed:9695949). {ECO:0000250|UniProtKB:P23188,
CC ECO:0000269|PubMed:9695949}.
CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network membrane
CC {ECO:0000250|UniProtKB:P09958}; Single-pass type I membrane protein
CC {ECO:0000305}. Cell membrane {ECO:0000250|UniProtKB:P09958}; Single-
CC pass type I membrane protein {ECO:0000305}. Secreted
CC {ECO:0000250|UniProtKB:Q28193}. Endosome membrane
CC {ECO:0000250|UniProtKB:P09958}; Single-pass type I membrane protein
CC {ECO:0000305}. Note=Shuttles between the trans-Golgi network and the
CC cell surface. Propeptide cleavage is a prerequisite for exit of furin
CC molecules out of the endoplasmic reticulum (ER). A second cleavage
CC within the propeptide occurs in the trans Golgi network (TGN), followed
CC by the release of the propeptide and the activation of furin.
CC {ECO:0000250|UniProtKB:P09958}.
CC -!- TISSUE SPECIFICITY: Cardiocytes (at protein level).
CC {ECO:0000269|PubMed:9252368}.
CC -!- INDUCTION: Up-regulated in cardiocytes in response to stretching for
CC 48hr. {ECO:0000269|PubMed:9252368}.
CC -!- DOMAIN: Contains a cytoplasmic domain responsible for its TGN
CC localization and recycling from the cell surface.
CC {ECO:0000250|UniProtKB:P09958}.
CC -!- PTM: The inhibition peptide, which plays the role of an intramolecular
CC chaperone, is autocatalytically removed in the endoplasmic reticulum
CC (ER) and remains non-covalently bound to furin as a potent
CC autoinhibitor. Following transport to the trans Golgi, a second
CC cleavage within the inhibition propeptide results in propeptide
CC dissociation and furin activation. {ECO:0000250|UniProtKB:P09958}.
CC -!- PTM: Phosphorylation is required for TGN localization of the
CC endoprotease. In vivo, exists as di-, mono- and non-phosphorylated
CC forms. {ECO:0000250|UniProtKB:P09958}.
CC -!- SIMILARITY: Belongs to the peptidase S8 family. Furin subfamily.
CC {ECO:0000305}.
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DR EMBL; X55660; CAA39193.1; -; mRNA.
DR PIR; S13106; KXRTF.
DR RefSeq; NP_062204.1; NM_019331.1.
DR AlphaFoldDB; P23377; -.
DR SMR; P23377; -.
DR STRING; 10116.ENSRNOP00000015521; -.
DR MEROPS; S08.071; -.
DR GlyGen; P23377; 3 sites.
DR PaxDb; P23377; -.
DR GeneID; 54281; -.
DR KEGG; rno:54281; -.
DR UCSC; RGD:3274; rat.
DR CTD; 5045; -.
DR RGD; 3274; Furin.
DR eggNOG; KOG3525; Eukaryota.
DR InParanoid; P23377; -.
DR PhylomeDB; P23377; -.
DR Reactome; R-RNO-1566948; Elastic fibre formation.
DR Reactome; R-RNO-1592389; Activation of Matrix Metalloproteinases.
DR Reactome; R-RNO-159782; Removal of aminoterminal propeptides from gamma-carboxylated proteins.
DR Reactome; R-RNO-167060; NGF processing.
DR Reactome; R-RNO-186797; Signaling by PDGF.
DR Reactome; R-RNO-2173789; TGF-beta receptor signaling activates SMADs.
DR Reactome; R-RNO-8963889; Assembly of active LPL and LIPC lipase complexes.
DR PRO; PR:P23377; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0009986; C:cell surface; ISO:RGD.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:RGD.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:RGD.
DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0031985; C:Golgi cisterna; IDA:RGD.
DR GO; GO:0000139; C:Golgi membrane; ISO:RGD.
DR GO; GO:0030173; C:integral component of Golgi membrane; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0045121; C:membrane raft; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0005802; C:trans-Golgi network; ISO:RGD.
DR GO; GO:0030140; C:trans-Golgi network transport vesicle; ISO:RGD.
DR GO; GO:0004175; F:endopeptidase activity; ISO:RGD.
DR GO; GO:1904399; F:heparan sulfate binding; ISS:UniProtKB.
DR GO; GO:0008201; F:heparin binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0048406; F:nerve growth factor binding; ISO:RGD.
DR GO; GO:0008233; F:peptidase activity; ISO:RGD.
DR GO; GO:0042277; F:peptide binding; ISO:RGD.
DR GO; GO:0002020; F:protease binding; ISO:RGD.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IMP:RGD.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; ISO:RGD.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0001825; P:blastocyst formation; ISO:RGD.
DR GO; GO:0090472; P:dibasic protein processing; ISO:RGD.
DR GO; GO:0032804; P:negative regulation of low-density lipoprotein particle receptor catabolic process; ISO:RGD.
DR GO; GO:0032911; P:negative regulation of transforming growth factor beta1 production; ISO:RGD.
DR GO; GO:0032902; P:nerve growth factor production; ISO:RGD.
DR GO; GO:0043043; P:peptide biosynthetic process; ISO:RGD.
DR GO; GO:0016486; P:peptide hormone processing; ISO:RGD.
DR GO; GO:0030335; P:positive regulation of cell migration; IMP:RGD.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IMP:RGD.
DR GO; GO:1901394; P:positive regulation of transforming growth factor beta1 activation; ISS:UniProtKB.
DR GO; GO:0016485; P:protein processing; IDA:RGD.
DR GO; GO:0032374; P:regulation of cholesterol transport; ISO:RGD.
DR GO; GO:0052548; P:regulation of endopeptidase activity; ISO:RGD.
DR GO; GO:0042176; P:regulation of protein catabolic process; ISO:RGD.
DR GO; GO:0009966; P:regulation of signal transduction; ISO:RGD.
DR GO; GO:0032940; P:secretion by cell; ISO:RGD.
DR GO; GO:0006465; P:signal peptide processing; ISO:RGD.
DR GO; GO:0019058; P:viral life cycle; ISO:RGD.
DR GO; GO:0031638; P:zymogen activation; ISO:RGD.
DR CDD; cd00064; FU; 2.
DR CDD; cd04059; Peptidases_S8_Protein_convertases_Kexins_Furin-like; 1.
DR Gene3D; 3.30.70.850; -; 1.
DR Gene3D; 3.40.50.200; -; 1.
DR InterPro; IPR006212; Furin_repeat.
DR InterPro; IPR008979; Galactose-bd-like_sf.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR034182; Kexin/furin.
DR InterPro; IPR002884; P_dom.
DR InterPro; IPR000209; Peptidase_S8/S53_dom.
DR InterPro; IPR036852; Peptidase_S8/S53_dom_sf.
DR InterPro; IPR023827; Peptidase_S8_Asp-AS.
DR InterPro; IPR022398; Peptidase_S8_His-AS.
DR InterPro; IPR023828; Peptidase_S8_Ser-AS.
DR InterPro; IPR015500; Peptidase_S8_subtilisin-rel.
DR InterPro; IPR032815; S8_pro-domain.
DR InterPro; IPR038466; S8_pro-domain_sf.
DR Pfam; PF01483; P_proprotein; 1.
DR Pfam; PF00082; Peptidase_S8; 1.
DR Pfam; PF16470; S8_pro-domain; 1.
DR PRINTS; PR00723; SUBTILISIN.
DR SMART; SM00261; FU; 2.
DR SUPFAM; SSF49785; SSF49785; 1.
DR SUPFAM; SSF52743; SSF52743; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR PROSITE; PS51829; P_HOMO_B; 1.
DR PROSITE; PS51892; SUBTILASE; 1.
DR PROSITE; PS00136; SUBTILASE_ASP; 1.
DR PROSITE; PS00137; SUBTILASE_HIS; 1.
DR PROSITE; PS00138; SUBTILASE_SER; 1.
PE 1: Evidence at protein level;
KW Autocatalytic cleavage; Calcium; Cell membrane;
KW Cleavage on pair of basic residues; Disulfide bond; Endosome; Glycoprotein;
KW Golgi apparatus; Heparin-binding; Hydrolase; Membrane; Metal-binding;
KW Phosphoprotein; Protease; Reference proteome; Repeat; Secreted;
KW Serine protease; Signal; Transmembrane; Transmembrane helix; Zymogen.
FT SIGNAL 1..26
FT /evidence="ECO:0000255"
FT PROPEP 27..107
FT /note="Inhibition peptide"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT /id="PRO_0000027032"
FT CHAIN 108..793
FT /note="Furin"
FT /id="PRO_0000027033"
FT TOPO_DOM 108..714
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 715..735
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 736..793
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 121..435
FT /note="Peptidase S8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT DOMAIN 444..576
FT /note="P/Homo B"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01173"
FT REPEAT 577..620
FT /note="FU 1"
FT /evidence="ECO:0000255"
FT REPEAT 638..681
FT /note="FU 2"
FT /evidence="ECO:0000255"
FT REGION 160..186
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 673..698
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 758..761
FT /note="Cell surface signal"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT REGION 766..793
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 498..500
FT /note="Cell attachment site"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00293"
FT MOTIF 772..778
FT /note="Trans Golgi network signal"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT COMPBIAS 673..688
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 153
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 194
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 368
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT BINDING 115
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 154
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 162
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 174
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 179
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 181
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 191..192
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 205
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 208
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 210
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 212
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 236
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 253..258
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 258
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 264
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 292..295
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 301
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 306
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 308
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 331
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 368
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT SITE 75..76
FT /note="Cleavage, second; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT SITE 107..108
FT /note="Cleavage, first; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT MOD_RES 772
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT MOD_RES 774
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT CARBOHYD 387
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 440
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 553
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 211..360
FT /evidence="ECO:0000250|UniProtKB:P23188"
FT DISULFID 303..333
FT /evidence="ECO:0000250|UniProtKB:P23188"
FT DISULFID 450..474
FT /evidence="ECO:0000250|UniProtKB:P23188"
SQ SEQUENCE 793 AA; 86653 MW; 87C22C345AE0A25C CRC64;
MELRPWLLWV VAAAGALVLL AAEARGQKIF TNTWAVHISG GPAVADSVAR KHGFHNLGQI
FGDYYHFWHR AVTKRSLSPH RPRHSRLQRV PQVKWLEQQV AKQRAKRDVY QEPTDPKFPQ
QWYLSGVTQR DLNVKEAWAQ GFTGRGIVVS ILDDGIEKNH PDLAGNYDPG ASFDVNDQDP
DPQPRYTQMN DNRHGTRCAG EVAAVANNGV CGVGVAYNAR IGGVRMLDGE VTDAVEARSL
GLNPNHIHIY SASWGPEDDG KTVDGPARLA EEAFFRGVSQ GRGGLGSIFV WASGNGGREH
DSCNCDGYTN SIYTLSISSA TQFGNVPWYS EACSSTLATT YSSGNQNEKQ IVTTDLRQKC
TESHTGTSAS APLAAGIIAL TLEANKNLTW RDMQHLVVQT SKPAHLNAND WATNGVGRKV
SHSYGYGLLD AGAMVALAQN WTTVAPQRKC IIEILAEPKD IGKRLEVRKT VTACLGEPNH
ISRLEHVQAR LTLSYNRRGD LAIHLISPMG TRSTLLAARP HDYSADGFND WAFMTTHSWD
EDPSGEWVLE IENTSEANNY GTLTKFTLVL YGTASEGLSA PPESSGCKTL TSSQACVVCE
EGFSLHQKSC VQRCPPGFTP QVLDTHYSTE NDVEIIRASV CTPCHASCAT CQGPAPTDCL
SCPSHASLDP VEQTCSRQSQ SSRESRPQQP PPALRPEVEV EPRLRAGLAS HLPEVLAGLS
CLIIALIFGI VFLFLHRCSG FSFRGVKVYT MDRGLISYKG LPPEAWQEEC PSDSEEDEGR
GERTAFIKDQ SAL
